CN113683579A - Method for synthesizing 1-phenyl-5-hydroxy tetrazole in continuous flow tubular reactor - Google Patents
Method for synthesizing 1-phenyl-5-hydroxy tetrazole in continuous flow tubular reactor Download PDFInfo
- Publication number
- CN113683579A CN113683579A CN202111160915.5A CN202111160915A CN113683579A CN 113683579 A CN113683579 A CN 113683579A CN 202111160915 A CN202111160915 A CN 202111160915A CN 113683579 A CN113683579 A CN 113683579A
- Authority
- CN
- China
- Prior art keywords
- continuous flow
- tubular reactor
- phenyl
- compound
- flow tubular
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing 1-phenyl-5-hydroxy tetrazole in a continuous flow tubular reactor. The method specifically comprises the following steps: in a continuous flow tubular reactor, phenyl isocyanate and trimethylsilyl azide are used as raw materials to synthesize a target product. The method adopts the continuous flow tubular reactor, greatly shortens the reaction time, has large contact area of reactants, high automation degree, convenient control, simplified post-treatment operation process, high efficiency, time and labor cost saving, yield of more than 95 percent, selectivity of the target product of 100 percent, reduction of the discharge of organic waste liquid and contribution to environmental protection.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for preparing 1-phenyl-5-hydroxy tetrazole.
Background
Rosuvastatin calcium, chemically known as bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2:1) and CAS number 147098-20-2, is a selective HMG-CoA reductase inhibitor developed and developed by the company asikang and marketed in various countries and regions of the united states, japan, europe, china, etc. The structural formula is as follows:
rosuvastatin calcium can be used for treating hyperlipidemia. In the production process, the compound is prepared by taking 1-phenyl-5-hydroxy tetrazole and the like as intermediates.
Currently, the following conventional process schemes (Journal of Organic Chemistry, 76 (1)), 2011, 216-. The total yield can reach 88 percent, but the method uses the traditional production equipment, the reaction time is dozens of hours, the operation process is complicated, and the process cost is higher.
Disclosure of Invention
The invention aims to provide a method for synthesizing 1-phenyl-5-hydroxy tetrazole in a continuous flow tubular reactor, which has the advantages of simplified reaction process, greatly shortened reaction time, high reaction efficiency and simple production equipment operation, and solves the problems of long reaction application time, complicated operation process and the like of the existing preparation process.
In order to achieve the purpose, the invention provides the following technical scheme:
the chemical structural formula of the 1-phenyl-5-hydroxy tetrazole is E1
. The method for preparing 1-phenyl-5-hydroxy tetrazole in the continuous flow tubular reactor is also applicable to the compounds:
the 1-phenyl-5-hydroxy tetrazole has two different structures due to tautomerism, and the two different structures are substantially the same substance.
Compound E1 was prepared in a continuous flow tubular reactor starting from phenyl isocyanate (compound a) and trimethylsilyl azide (compound b) according to the following reaction scheme:
the method for preparing the 1-phenyl-5-hydroxy tetrazole in the continuous flow tubular reactor comprises the following steps:
preparation of Material A: adding phenyl isocyanate into DMF, and stirring to mix uniformly;
preparing a material B: adding azido trimethyl silane into DMF, and stirring to uniformly mix;
respectively introducing the materials A, B into a preheater for preheating, wherein the set temperature is controlled by an external heat exchanger;
the feeding molar ratio of the compound a to the compound b is changed to be 1: (0.62 to 4.35), conveying the two materials together into the continuous flow tubular reactor 1, mixing the materials at a specific temperature, and reacting for 12 to 150 seconds; the reaction temperature is 40-80 ℃, and the set temperature is controlled by an external heat exchanger; the heat exchange medium I is heat conduction oil or water;
cooling the reacted product to room temperature through a cooling coil 3 and concentrating, wherein a heat exchange medium II is water or an ice-water mixture and enters a post-treatment stage;
and diluting, adjusting the pH value, extracting and drying the reacted materials to obtain the target compound E1.
The feeding molar ratio of the compound a to the compound b is 1: 1.05; the reaction temperature is 63 +/-3 ℃; the reaction time was 62 s.
The continuous flow tubular reactor system comprises three parts of raw material preheating, mixed reaction and product cooling, so that three modules of a raw material preheater, a tubular reactor and a cooling coil are required, wherein the length of the tubular reactor is determined by the reaction time. The connection mode of the three modules is as follows: the two raw material preheaters are connected in parallel, then connected in series with the tubular reactor and then connected in series with the cooling coil.
In the invention, the tubular reactor and the cooling coil are both in a spiral tubular structure, which is beneficial to increasing the contact area between reactants so as to ensure more complete reaction.
In the preparation method disclosed by the invention, no by-product is generated, so that no reagent is required to be added for removing the by-product, and the production process further simplifies the post-treatment operation process. Compared with the prior art, the invention has the beneficial effects that:
(1) the invention adopts the continuous flow tubular reactor, the whole reaction process only needs a few seconds to a few minutes, and the reaction time is greatly shortened; but also can increase the contact area of materials, so that reactants are completely converted, and the conversion rate, the yield and the product selectivity are higher;
(2) the equipment is simple to operate, the reaction rate is high, and the time and the labor cost are saved;
(3) in the preparation method, no by-product is generated, so that no reagent is required to be added to remove the by-product, and the production process further simplifies the post-treatment operation process;
(4) the method of the invention has the advantages of less time consumption in the whole process, reduced discharge of organic waste liquid and more environmental friendliness.
Drawings
FIG. 1 is a diagram of a continuous flow tubular reactor system apparatus used in the present invention; 1-tubular reactor, 21-heat exchange medium I, 22-heat exchange medium II, 3-cooling coil.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The length of the tubular reactor is determined according to the reaction time, the heat exchange medium I is heat conduction oil, and the heat exchange medium II is an ice-water mixture.
Preparation of Material A: adding 595g of phenyl isocyanate (5 mol) into DMF (800 mL), stirring to uniformly mix the phenyl isocyanate and the DMF, and placing the mixture into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a tubular reactor through a valve) for later use;
preparing a material B: taking azidotrimethylsilane (575 g, 5 mol), adding into DMF (800 mL), stirring to mix uniformly, and placing into a raw material tank B (the bottom of which is connected with a corresponding feed pipeline of a tubular reactor through a valve) for standby;
opening valves at the bottoms of the material tanks A and B, respectively conveying the material A, B to a preheater for preheating through a plunger pump, and setting the temperature of a heat exchanger to be 63 ℃ so as to preheat the material to be 63 +/-3 ℃;
the volumetric flow rate ratio of the feedstock A, B was set to 16.3: 20.7, the molar ratio of the phenyl isocyanate to the trimethylsilyl azide is 1: 1.05.
Feed A, B was fed to a continuous flow tubular reactor, mixed at 63 ± 3 ℃ and reacted for 62 s.
And cooling the product after reaction to room temperature through a cooling coil, concentrating, and entering a post-treatment stage.
Taking a proper amount of residues for post-treatment for multiple times: diluting with ethyl acetate (100mL), adding 6M hydrochloric acid dropwise to the mixed aqueous layer while stirring, adjusting pH to <3, extracting with ethyl acetate (3X 200mL), drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound E1 as a white solid, with a conversion of 98.5% of phenyl isocyanate, a yield of 95.3%, and a selectivity of E1 of 100%.
Examples 2 to 9
Only the feed ratio or other conditions were changed, respectively, in the manner disclosed in example 1, detailed in table 1.
Note: the white portion in the table represents that the conditions are the same as in example 1.
Table 1 different reaction conditions and results
| Examples | na：nb | Reaction temperature/. degree.C | Reaction time/s | Conversion rate/% | Yield/% | Target product selectivity/%) |
| 1 | 1:1.05 | 63 | 62 | 98.5 | 95.3 | 100 |
| 2 | 1:2.5 | 98.2 | 93.3 | 100 | ||
| 3 | 1:0.62 | 96.5 | 90.3 | 100 | ||
| 4 | 1:4.35 | 96.3 | 93.6 | 100 | ||
| 5 | 40 | 82.2 | 89.2 | 100 | ||
| 6 | 80 | 98.4 | 91.7 | 100 | ||
| 7 | 12 | 85.7 | 89.4 | 100 | ||
| 8 | 150 | 96.1 | 94.3 | 100 | ||
| 9 | 130 | 95.5 | 93.5 | 100 |
Comparative example 1
PCT patent WO 2020150210a1 reports the following preparation process: a stirred mixture of phenyl isocyanate (1.0g, 8.4 mmol, 1.0 eg) and azidotrimethylsilane (3.0 ml, 22.5 mmol, 2.7 eq) was heated to 100 ℃ and stirred for 16 h. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (10 mL) and extracted with saturated aqueous sodium bicarbonate (3X 10 mL). While stirring, 6M hydrochloric acid was added, the pH was adjusted to <3, and extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 32 (1.0g, 74%) as a white solid.
Comparative example 2
The following preparation processes are reported in the literature (Medicinal Chemistry Research, 22(7), 2013, 3329-: trimethylsilyl azide (1.80 g, 15.6 mmol) and phenyl isocyanate (1.86 g, 15.6 mmol) were dissolved in dry benzene (5 ml), stirred at 50-60 ℃ under nitrogen for 24 h, evaporated in vacuo, and the residue was recrystallized from benzene to give 1-phenyl-5-hydroxytetrazol in 88% yield.
According to the data, the reaction time of the traditional preparation process is as long as 16-24 hours, the yield is only 88% at most, the yield of the preparation process in the application can be as high as 95% within tens of seconds, and the minimum yield is 89.4%. Therefore, the production efficiency is greatly improved by using the preparation process.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A method for synthesizing 1-phenyl-5-hydroxy tetrazole in a continuous flow tubular reactor, wherein the chemical structural formula of the 1-phenyl-5-hydroxy tetrazole is E1
The method is characterized in that: in a continuous flow tubular formIn a reactor, phenyl isocyanate (compound a) and trimethylsilyl azide (compound b) are used as raw materials to prepare a compound E1, and the reaction formula is as follows:
the method comprises the following steps:
step (1): adding phenyl isocyanate into N, N-dimethylformamide, and stirring to uniformly mix to obtain a material A;
step (2): adding azido trimethyl silane into N, N-dimethylformamide, and stirring to uniformly mix to obtain a material B;
and (3): respectively introducing materials A, B into a preheater for preheating, wherein the set temperature is controlled by a heat exchange medium I in the preheater;
and (4): changing the feeding amount of the compound a and the compound b of the preheated material obtained in the step (3) through a counting pump, conveying the materials into the continuous flow tubular reactor (1) together, controlling the set temperature by a heat exchange medium I in the continuous flow tubular reactor, mixing and reacting;
and (5): cooling the reaction liquid reacted in the step (4) to 20-25 ℃ through a cooling coil (3), cooling the reaction liquid by a heat exchange medium II outside the cooling coil, transferring the cooled reaction liquid into a reaction kettle for concentration, and entering a post-treatment stage;
and (6): and (5) diluting the material concentrated in the step (5), adjusting the pH value, extracting and drying to obtain a target compound E1.
2. The process for the synthesis of 1-phenyl-5-hydroxytetrazole in a continuous flow tubular reactor according to claim 1, wherein: in the step (3), the temperature of the preheater is 40-80 ℃, and the heat exchange medium I is heat conduction oil or water.
3. The process for the synthesis of 1-phenyl-5-hydroxytetrazole in a continuous flow tubular reactor according to claim 2, wherein: in the step (4), the feeding molar ratio of the compound a to the compound b is 1: (0.62-4.35); the reaction temperature is 40-80 ℃; the reaction time is 12-150 s.
4. The process for the synthesis of 1-phenyl-5-hydroxytetrazole in a continuous flow tubular reactor according to claim 2, wherein: in the step (3), the temperature of the preheater is 63 +/-3 ℃.
5. The process for the synthesis of 1-phenyl-5-hydroxytetrazole in a continuous flow tubular reactor according to claim 4, wherein: in the step (4), the feeding molar ratio of the compound a to the compound b is 1: 1.05; the reaction temperature is 63 +/-3 ℃; the reaction time was 62 s.
6. The process for the synthesis of 1-phenyl-5-hydroxytetrazole in a continuous flow tubular reactor according to any of claims 1 to 5, characterized in that: in the step (5), the heat exchange medium II is water or an ice-water mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111160915.5A CN113683579A (en) | 2021-09-30 | 2021-09-30 | Method for synthesizing 1-phenyl-5-hydroxy tetrazole in continuous flow tubular reactor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111160915.5A CN113683579A (en) | 2021-09-30 | 2021-09-30 | Method for synthesizing 1-phenyl-5-hydroxy tetrazole in continuous flow tubular reactor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113683579A true CN113683579A (en) | 2021-11-23 |
Family
ID=78587510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111160915.5A Pending CN113683579A (en) | 2021-09-30 | 2021-09-30 | Method for synthesizing 1-phenyl-5-hydroxy tetrazole in continuous flow tubular reactor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113683579A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113301901A (en) * | 2019-01-14 | 2021-08-24 | 北京轩义医药科技有限公司 | Tetrazolinone substituted steroids and uses thereof |
-
2021
- 2021-09-30 CN CN202111160915.5A patent/CN113683579A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113301901A (en) * | 2019-01-14 | 2021-08-24 | 北京轩义医药科技有限公司 | Tetrazolinone substituted steroids and uses thereof |
Non-Patent Citations (3)
| Title |
|---|
| 刘全等: "连续流反应技术在药物分子合成中的研究进展", 《安徽化工》 * |
| 吕利霞等: "《化工反应实训》", 31 December 2013 * |
| 许春树等: "《化工设备使用与维护》", 31 December 2012 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105541845B (en) | Folic acid cleanly production technique | |
| CN114573560B (en) | Preparation method of voronoi fumarate | |
| CN111704555A (en) | Method for synthesizing 4-methoxy-2-nitroaniline by adopting continuous flow reactor | |
| WO2021179921A2 (en) | Method for using continuous tank reactor to prepare imidazole | |
| CN111004162B (en) | Method and device for preparing L-selenocysteine by using sodium triacetoxyborohydride as reducing agent | |
| CN104119243B (en) | A kind of energy-saving clean production method of iminodiethanoic acid | |
| CN110183358A (en) | Hydrazine hydrochloride is as the purposes of production aminoguanidine carbonate and the combine production method of aminoguanidine carbonate and ammonium chloride | |
| CN113683579A (en) | Method for synthesizing 1-phenyl-5-hydroxy tetrazole in continuous flow tubular reactor | |
| CN111995640A (en) | Method for synthesizing (3-amino-3-cyano) propyl methyl butyl phosphite based on microchannel reactor | |
| CN109516960B (en) | Preparation method of urapidil hydrochloride | |
| CN115536595B (en) | Synthesis method of 2-amino-4, 6-dichloro-5-formamido pyrimidine | |
| CN103896858A (en) | Technology for preparing cytosine | |
| CN115073389B (en) | Energy-saving melamine production system and production method | |
| CN113801072A (en) | Method for synthesizing rosuvastatin calcium intermediate in continuous flow tubular reactor | |
| CN109761916A (en) | A kind of improvement synthetic method of orotic acid | |
| CN108912019A (en) | The method that one kind recycling mantoquita and ethyl alcohol from D, L- Su Shi-D-4-methylsulfonylphserine serine ethyl ester mother liquor | |
| CN113831295B (en) | Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor | |
| CN112358404A (en) | Preparation method of 2-chloro-6-methylaniline | |
| CN110577496A (en) | Preparation method of uracil | |
| CN114292297B (en) | Method for preparing antiviral drug tenofovir alafenamide fumarate | |
| CN111499622A (en) | Preparation method of medicine for treating bile duct cancer | |
| CN218710089U (en) | Device for producing tetramethyl piperidone through continuous catalytic synthesis | |
| CN113651751B (en) | Preparation method of N-methoxycarbonyl-3-trifluoromethylpyridine-2-sulfonamide | |
| CN114805218B (en) | Preparation method of rosuvastatin calcium intermediate | |
| CN108774231A (en) | A kind of environment-protection production method of folic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20211123 |
|
| WD01 | Invention patent application deemed withdrawn after publication |